T he evolution of the statin class of drugs has made a substantial contribution to the management of hyperlipidemia. Since the initial release of this category of agents in the mid-1980s, excellent efficacy in low density lipoprotein cholesterol (LDL-C) lowering has been reported with minimal or few side effects. Moreover, both primary and secondary prevention trials have demonstrated substantial coronary heart disease risk reduction in individuals consuming these pharmaceutical preparations. The high density lipoprotein cholesterol (HDL-C) raising action of certain members of the statin class of drugs has also been increasingly recognized. Results from such trials are highly impressive; the overall lipid-modulatory efficacy of this class of drug translates into reductions in non-fatal myocardial infarction and coronary death of about 25%, improving quality of life and longevity among users. The mechanism of action of the statin class of drugs has been thought to exist through suppression of the enzyme regarded as key in the regulation of the pathway of cholesterol synthesis, 3-methylglutaryl-coenzyme A-reductase (HMG CoA reductase) activity. Reductase activity is inhibited by statin treatment, as is whole body cholesterol synthesis rate. It is often underappreciated that whole body synthesis rates for cholesterol amounts to up to 1 g per day, compared with perhaps 200 to 400 mg/day absorbed from food. In view of this large daily contribution of sterol synthesis to whole body cholesterol input, the remarkable efficacy of statin drugs in suppressing circulating cholesterol is perhaps not so surprising. Despite existing knowledge about mechanisms of action of statins, less is clear about the safety of long term use. Some controversy exists regarding the prevalence of side effects; although some previous intervention trials reported similar occurrences between cases and controls of unexplained muscle pain or weakness or other adverse effects, a recent Danish study claimed that statin use was associated with incidence of neurological effects at one year of 15% and two or more years at 27%. These results underscore the need for a better understanding of the metabolic sequelae to use of statins in the management of hypercholesterolemia over the longer term. To this end, Papu, Bacon, and Illingworth in this issue addresses the question of whether metabolic upregulation of the HMG CoA reductase enzyme and its pathway occur after cessation of statins following 8 weeks of use. Results from the clinical trial described in their report show that termination of treatment with lovastatin or simvastatin therapy results in a rapid but transitory rise in cholesterol synthesis, but no prolonged increase in cholesterogenesis or plasma lipid levels. The authors conclude that cessation of statin therapy does not result in adverse metabolic effects. The paper thus provides further evidence of safety for the statin class of drugs, particularly when larger or more prolonged dosages are contemplated. The study makes an important contribution in that the unique methodology of measuring cholesterol synthesis rate overcomes a key limitation of the area. This limitation is the fact that methods of measuring cholesterol biosynthesis have been unavailable as they are either direct but overly invasive, or indirect but inaccurate. Existing methodologies for assessment of whole body cholesterol synthesis fall into three categories: (1) balance, (2) isotopic kinetic, and (3) precursor assessment techniques. Sterol balance has existed as the gold standard for several decades; this is defined as the amount of whole body synthesis calculated as the difference between amount of cholesterol excreted and that consumed. Although straightforward, sterol balance is dependent on accuracy in measurement of fecal excretion and dietary intake of cholesterol. Alternatively, isotopic means of assessing cholesterol synthesis including mass isotopomer distribution analysis and deuterium incorporation require assumptions about the model used, and are invasive and time consuming. The third approach, determination of precursor levels in J Lab Clin Med 2003;141:235-6. Copyright © 2003 by Mosby, Inc. All rights reserved. 0022-2143/2003 $30.00 0 doi:10.1067/mlc.2003.34
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